P1131: POST HOC ANALYSIS OF PATIENTS WITH HIGHLY PROLIFERATIVE VARIANTS OF MANTLE CELL LYMPHOMA TREATED WITH ACALABRUTINIB
Authors: S. Le Gouill, M. Długosz-Danecka, S. Rule, P. Luigi Zinzani, A. Goy, S. D. Smith, J. K. Doorduijn, C. Panizo, B. Shah, A. Davies, R. Eek, E. Jacobsen, A. P. Kater, T. Robak, P. Jain, R. Calvo, H. Yang, M. Wang
Journal: HemaSphere (2022)

Background: Blastoid and pleomorphic variants of mantle cell lymphoma (MCL) are considered high risk and have poor prognoses. Patients with these variants rarely achieve durable remission or prolonged clinical outcomes with currently available chemotherapies and targeted therapies. Final results from ACE-LY-004, an open-label, multicenter, single-arm phase 2 study of the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib in adult patients with relapsed/refractory (R/R) MCL confirmed acalabrutinib was highly active in patients with R/R MCL, with a median overall survival of 59.2 months, a median progression-free survival (PFS) of 22.0 months, and a median duration of response (DOR) of 28.6 months after a median 38.1 months of follow-up. In a subgroup analysis, we found that patients with 1 prior line of therapy had unexpectedly shorter DOR than those who had ≥2 prior lines of therapy. Aims: To investigate a possible reason for shorter DOR in patients with R/R MCL treated with acalabrutinib who received only 1 prior line of therapy, we conducted a post hoc analysis on a subgroup of patients with blastoid/pleomorphic disease. Methods: ACE-LY-004 enrolled adult patients with confirmed R/R MCL and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2. Informed consent was obtained. Acalabrutinib 100 mg was administered orally twice daily until occurrence of progressive disease or unacceptable toxicity. Results: A total of 124 patients were enrolled; median age was 68 years and 80% of patients were male. As of December 4, 2020, median follow-up was 38.1 months and median treatment exposure was 17.5 months (range 0.1–65.3). Fifty-nine of the 124 patients (48%) had 1 prior therapy. The remaining 65 patients (52%) had 2 prior therapies (n=37) or ≥3 prior therapies (n=28). Median DOR was longer in patients with ≥2 prior lines of therapy versus those with 1 prior therapy (33.8 and 25.6 months, respectively). Similarly, median PFS was longer in patients who received acalabrutinib in later lines of therapy than in those who received acalabrutinib as second-line therapy (24.8 and 19.2 months, respectively). Among the 59 patients with 1 prior therapy, 16 (27%) had blastoid or pleomorphic disease and 43 (73%) did not, compared with 10 patients (15%) with blastoid/pleomorphic disease and 55 (85%) who did not among the 65 patients with ≥2 prior therapies. Overall response rate (ORR) in those with 1 prior therapy was 88% (n=14; 95% CI 61.7–98.4) in those with blastoid/pleomorphic disease (complete response [CR] in 50%, n=8) versus 81% (n=35; 95% CI 66.6–91.6) in those without blastoid/pleomorphic disease (CR in 47%, n=20). Median DOR for these patients was 20.3 (95% CI 3.5–46.9) and 31.8 (95% CI 14.9–not estimable) months, respectively. Summary/Conclusion: In this post hoc analysis of the ACE-LY-004 study of acalabrutinib in adult patients with confirmed R/R MCL, a shorter DOR was observed among patients who received acalabrutinib after 1 prior therapy compared with those who received acalabrutinib after ≥2 prior therapies, likely explained by a high proportion of patients with blastoid/pleomorphic variants in the group of patients receiving acalabrutinib after 1 prior therapy. While patients with blastoid/pleomorphic variant had comparable ORR, DOR was shorter but still substantial at 20.3 months, indicating that some patients with highly proliferative disease and poorer prognosis also achieve clinical benefit from acalabrutinib.